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Enhancement of glucose-stimulated insulin secretion by cells through induction of cellular senescence

a technology of senescence and glucose stimulation, which is applied in the field of induction of cellular senescence, can solve the problems of reducing the proliferative capacity of -cells, aging tissues typically display, and deteriorating overall function,

Inactive Publication Date: 2017-07-13
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new discovery that a marker of cellular aging can increase the amount of insulin released from beta cells in response to glucose. This discovery also suggests that inducing cellular aging in beta cells can improve glucose control in an entire organism.

Problems solved by technology

Aged tissues typically display decreased regenerative capacity and deterioration in overall function.
The proliferative capacity of β-cells declines dramatically at an early age, potentially contributing to overall reduced β-cell mass and increased risk of diabetes.
However, it is not known whether the age-associated increase in p16-expression leads to senescence of β-cells, or whether such cells remain functional in glucose sensing and insulin secretion.

Method used

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  • Enhancement of glucose-stimulated insulin secretion by cells through induction of cellular senescence
  • Enhancement of glucose-stimulated insulin secretion by cells through induction of cellular senescence
  • Enhancement of glucose-stimulated insulin secretion by cells through induction of cellular senescence

Examples

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Effect test

example 1

es Cell-Cycle Arrest and Senescence in Pancreatic β-Cells

[0152]To study the effects of p16 expression in β-cells mice carrying a tetracycline-inducible human p16 transgene (tet-p16) and crossed them with mice expressing the reverse tetracycline-dependent transactivator under control of the insulin II promoter (Insulin-rtTA) were generated, thus allowing β-cell specific p16 activation upon tetracycline (tet) treatment. In mice treated for 10 days starting at 3-4 weeks of age, transgenic p16 was detected by immunostaining in ˜35% of β-cells; lower-level expression in additional cells could not be excluded (FIGS. 1A-B and FIG. 2A, C). Ki67 staining revealed that 3.5% of β-cells in control mice were proliferating, whereas p16-expressing β-cells were non-proliferative (FIG. 1B-C). Senescence-associated β-galactosidase (SA-βGal) activity and the expression of the lysosomal marker Lamp2a were increased in p16-expressing islets, indicating that p16 induces features of senescence (FIG. 1D-E)...

example 2

ssing β-Cells Express Senescence Genes and Genes Associated with Functional Maturation

[0153]To isolate a population of β-cells enriched for p16 expression, triple-transgenic mice carrying a tet-GFP transgene in addition to tet-p16 and Insulin-rtTA were generated, such that GFP and p16 are co-activated in a largely overlapping subset of β-cells. The mice were treated with tet for 10 days, their islets were dissected and dissociated, and GFP-positive cells were isolated by FACS (FIG. 2C-D). The transcriptome of these cells was compared to that of control β-cells isolated from mice expressing only the GFP transgene (FIG. 2D). It was found that genes associated with cell proliferation were suppressed in p16-expressing β-cells; in contrast, gene sets previously shown to be elevated in senescent cells were significantly upregulated by p16 expression (FIG. 1K-M). Strikingly, these sets were derived from diverse biological settings, including chemotherapy-treated lymphoma cells, Ras-express...

example 3

ases Glucose-Stimulated Insulin Secretion

[0157]To directly study the effect of p16 expression on β-cell function, pancreatic islets were isolated from p16-expressing and control mice following 10 days of tet treatment starting at 4 weeks of age, and measured glucose stimulated insulin secretion (GSIS). While the levels of insulin secreted from islets at low glucose did not significantly differ between p16-expressing and control islets, p16-expressing islets secreted approximately 2.5-fold more insulin upon glucose stimulation (FIG. 5A). This increase was evident when secreted insulin levels were normalized either to total insulin or to protein content in the islet samples (FIG. 5A and FIG. 6A). Normalization of insulin levels directly to β-cell number, scored by FACS, also indicated that secretion per β-cell was elevated (FIG. 5B). GSIS remained high in p16-expressing islets after two months of p16 induction, indicating that this represented a stable phenotypic change (FIG. 5C). Act...

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Abstract

Methods for increasing glucose induced insulin secretion in an insulin secreting cell by inducing senescence in the cell are provided. Further, methods for treating diabetes, by providing cells with increased glucose induced insulin secretion to a subject, as well as a population of modified insulin secreting cells are provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 275,836, filed Jan. 7, 2016, the contents of which are incorporated herein by reference in their entirety.FIELD OF INVENTION[0002]The present invention is directed to the field insulin secreting cells and methods of use thereof.BACKGROUND OF THE INVENTION[0003]Aged tissues typically display decreased regenerative capacity and deterioration in overall function. Cellular senescence is thought to contribute to tissue aging and associated pathologies by various means, including limitation of stem cell proliferation and enhanced secretion of negatively-acting paracrine factors. Senescence is often activated in damaged cells, and senescent cells accumulate in aging tissues as well as in premalignant lesions. However, recent studies have also demonstrated roles for senescence in normal embryonic development, expanding the traditional view of its functio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/39A61K38/28C12N5/071
CPCA61K35/39C12N5/0676A61K38/28C12N2501/998A61K38/00C07K14/62C12N2501/405C12N2740/15043
Inventor BEN-PORATH, ITTAIDOR, YUVALHELMAN, AHARONKLOCHENDLER, AGNES
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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